CD8 positive cytotoxic T lymphocytes (CTLs) have been shown to recognize epitope peptides derived from the tumor-associated antigens (TAAs) found on the major histocompatibility complex (MHC) class I molecule, and then kill the tumor cells. Since the discovery of the melanoma antigen (MAGE) family as the first example of TAAs, many other TAAs have been discovered, primarily through immunological approaches (NPL 1, 2). Some of these TAAs are currently undergoing clinical development as immunotherapeutic targets.
TAAs which are indispensable for proliferation and survival of cancer cells are valiant as targets for immunotherapy, because the use of such TAAs may minimize the well-described risk of immune escape of cancer cells attributable to deletion, mutation, or down-regulation of TAAs as a consequence of therapeutically driven immune selection.
Accordingly, the identification of new TAAs capable of inducing potent and specific anti-tumor immune responses, warrants further development. Thus, the clinical application of peptide vaccination strategies for various types of cancer is ongoing (NPL 3-10). To date, there have been several reports of clinical trials using these tumor-associated antigen derived peptides. Unfortunately, so far, these cancer vaccine trials have yielded only a low objective response rate has been observed in these cancer vaccine trials so far (NPL 11-13). Accordingly, there remains a need in the art for new TAAs suitable for use as immunotherapeutic targets.
LY6K was initially identified by several groups (Accession No. NM_017527; SEQ ID NO: 8 encoded by SEQ ID NO: 7) as an unannotated transcript. More recent analysis by bioinformatics classified it as a member belonging to the LY6 family having a high homology to the low molecular-weight GPI-anchored molecule (NPL 14). Like others in the LY6 family, LY6K has 10 cysteine residues in a conserved position and harbors the sequence structure that, in theory, determines GPI anchoring. Members of the LY6 family believed to possess functions related to cell signaling and/or cell adhesion (NPL 15), although the precise role of LY6K in lung carcinogenesis or its physiological function in normal cells is presently unknown. Since the LY6K gene is located at chromosome 8q24, a region of allelic gain in more than half of lung cancers (NPL 16), its over-expression may result from amplification or chromosomal aberration at this locus.
Through gene expression profile analysis using a genome-wide cDNA microarray containing 23,040 genes, LY6K was recently shown to be up-regulated in several cancers such as bladder cancer, cervical cancer, cholangiocellular carcinoma, esophageal cancer, gastric cancer, non-small cell lung cancer (NSCLC), osteosarcoma, pancreatic cancer and soft tissue tumor (PTL 1, PTL 2, PTL 3).
Taken together, this data suggests that LY6K is a novel, potentially universal on-coantigen. Accordingly, epitope peptides derived from LY6K may be applicable as cancer immunotherapeutics for the treatment of a wide array of cancers.
Recently, highly immunogenic LY6K-derived cytotoxic T lymphocytes (CTL)-epitopes that can induce tumor-reactive and HLA-A2 (A*02:01)-restricted CTL from PBMCs of healthy volunteers (PTL 1) have been identified. Furthermore, LY6K-derived HLA-A24-restricted CTL-epitopes have been also identified (NPL 17, PTL 4). Therefore, LY6K remains an attractive target molecule applicable to cancer immunotherapy.
Tumor-specific CD4+ helper T (Th) cells, especially T-helper type 1 (Th1) cells play a critical role in efficient induction of CTL-mediated antitumor immunity (NPL 18). The IFN-gamma primarily produced by Th1 cells is critical for induction and maintenance of long lived CTL responses by providing help through multiple interactions, which are critical in the preservation of immunological memory (NPL 19, 20). The IFN-gamma secreted by Th1 cells also mediates direct antitumor or anti-angiogenic effect (NPL 21). Furthermore, it has been shown that Th cells must pave the way for entry of CTLs at tumor site (NPL 22). Therefore, identification of tumor-associated antigen (TAA)-derived Th cell epitopes that can activate specific Th1 cell is important for induction of an effective tumor immunity in tumor-bearing hosts; ideally, the design of effective vaccines should include multiple epitopes to stimulate both CTL and Th1 cells (NPL 23). However, no such epitope derived from LY6K has yet been identified.